The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). To assess distribution and longitudinal changes of SARA scores and its single items, the authors analyzed SARA scores of 502 patients with typical-onset FA (<25 years) participating in the 4-year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed-effects regression models. The chosen statistical model was re-fitted in order to estimate parameters and predict disease progression. Median time-to-change and rate of score progression were estimated using the Kaplan-Meier method and weighted linear regression models, respectively. SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4-year follow-up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one-point score increase of 1 to 2 years. Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials.
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Scientific News
FARA funds research progress
In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA's Grant Program and the Treatment Pipeline.
Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset
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SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin
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Efferocytosis is an activity of macrophages that is pivotal for the resolution of inflammation in hypertension. The precise mechanism by which macrophages coordinate efferocytosis and internalize apoptotic cardiomyocytes remains unknown. The aim of this study was to determine whether SIRT3 (sirtuin-3) is required for both apoptotic cardiomyocyte engulfment and anti-inflammatory responses during efferocytosis. The authors generated myeloid SIRT3 knockout mice and knock-in mice carrying an acetylation-defective lysine to arginine K189R mutation (FXNK189R). The mice were given Ang II (angiotensin II) infusion for 7 days. Cardiac macrophages' mitochondrial iron levels, efferocytosis activity, and phenotype both in vivo and in vitro were analyzed. SIRT3 deficiency exacerbated Ang II-induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN (frataxin) at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXN K189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXNK189R mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis. The SIRT3-FXN axis has the potential to resolve cardiac inflammation by increasing macrophage efferocytosis and anti-inflammatory activities.
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Structural aspects of enzymes involved in prokaryotic Gram-positive heme biosynthesis
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The coproporphyrin dependent heme biosynthesis pathway is almost exclusively utilized by Gram-positive bacteria. This fact makes it a worthwhile topic for basic research, since a fundamental understanding of a metabolic pathway is necessary to translate the focus towards medical biotechnology, which is very relevant in this specific case, considering the need for new antibiotic targets to counteract the pathogenicity of Gram-positive superbugs. Over the years a lot of structural data on the set of enzymes acting in Gram-positive heme biosynthesis has accumulated in the Protein Database - www.pdb.org. One major challenge is to filter and analyze all available structural information in sufficient detail in order to be helpful and to draw conclusions. Here the authors give a holistic overview of structural information on enzymes involved in the coproporphyrin dependent heme biosynthesis pathway. There are many aspects to be extracted from experimentally determined structures regarding the reaction mechanisms, where the smallest variation of the position of an amino acid residue might be important, but also on a larger level regarding protein-protein interactions, where the focus has to be on surface characteristics and subunit (secondary) structural elements and oligomerization. This review delivers a status quo, highlights still missing information, and formulates future research endeavors in order to better understand prokaryotic heme biosynthesis.
Trinucleotide Repeat Disorders
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Trinucleotide repeat disorders consist of a group of human diseases that are a result of an abnormal expansion of repetitive sequences and primarily affect the nervous system. These occur during various stages of human development. Repetitive sequences, scattered in the microsatellite regions, usually account for about 30% of the human genome. In a normal person, the main purpose of various lengths of repetitive DNA is to allow for evolutionary plasticity. However, when these repeats extend beyond the code for a viable physiological protein, the expression of this aberrant segment is suppressed. After a certain threshold number, this suppression is lost, and an aberrant protein is coded for, which gives rise to either a functional or a non-functional protein, thereby giving rise to a 'gain of function' or 'loss of function' mutation. With every generation, the number of repeats increases drastically, and the age at which the patient presents is inversely related to the number of expansions. The severity, on the other hand, worsens with every generation due to a larger repeat sequence. Thus, the inheritance pattern of the repeat expansion diseases is evidence of the dynamic nature of these mutations and is termed 'anticipation. This article will study the various parameters of trinucleotide repeat disorders by reviewing in detail the five most commonly studied disorders.
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Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia
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The screening of twenty different agonist compounds was carried out in order to find the most promising agonist compound that may be used for molecular docking prediction against the Frataxin Protein. The compound with the lowest binding energies is then optimized by halogens. The final candidate's drug-like properties are identified through Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling. Lipinski's rule of five was checked. Molecular dynamic stimulations were evaluated. The most potent agonist compound was identified out of twenty different compounds utilizing a docking approach against the Frataxin Protein. The compound with the lowest binding energies was next subjected to optimization by halogens. The optimized agonist 9-[1-[(1S, 5R)-8, 8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl]triazol-4-yl]fluoren-9-ol has higher binding energy of -10.4Kcal/mol with molecular weight of 705.63 g/mol. Drug-like properties are identified through ADMET profiling, having water solubility of about -7.59, skin permeation -7.08 cm/s, bioavailability score 0.17, and high GI absorption. The candidate fulfills the Lipinski rule of five and portrays efficient molecular dynamic stimulations.
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- BDNF and Cerebellar Ataxia
- PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients
- Proteomic Investigation of Differential Interactomes of Glypican 1 and a Putative Disease-Modifying Variant of Ataxia
- Patient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health app
- Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia